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Plasma anion gap

Plasma anion gap


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Plasma anion gap

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USMLE® Step 1 style questions USMLE

2 questions

A 44-year-old woman comes to the clinic with fatigue, weight loss, and nausea. Over the past six months, she has felt her energy gradually decrease, and she now gets tired walking one city block. She has lost her appetite for most foods except french fries and potato chips. Every few days, she experiences a wave of nausea and cramping abdominal pain that causes her to vomit. Family history is significant for autoimmune hypothyroidism in her mother. His/her temperature is 37.0°C (98.6°F), pulse is 80/min, respirations are 18/min, and blood pressure is 90/60 mmHg. Physical examination shows a thin female with a non-distended, minimally tender abdomen. Oral examination shows the following:  

Reproduced from: Wikimedia Commons  

Laboratory studies show the following:  

 Laboratory value  Result 
 Sodium   130 mEq/L 
 Potassium   6.0 mEq/L 
 Chloride   100 mEq/L 
 Bicarbonate  18 mEq/L 
 pH  7.31 
 pH  5.0 

 Which of the following is the most likely explanation for these findings?  

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Rishi Desai, MD, MPH

Plasma anion gap is a measurement of the balance between positively charged ions called cations and negatively charged ions called anions, within the plasma.

Its normal range is typically between 3 and 11 mEq/L, while anything below 3 mEq/L is considered abnormally low, and above 11 mEq/L is usually considered abnormally high, and.

Every single moment, trillions of cations and anions are floating around inside our blood vessels. For them to happily and stably coexist, the plasma has to be kept electrically neutral.

That means that the sum of all positive charge from cations has to equal the sum of all negative charge from anions.

The vast majority of cations are sodium Na+ ions, followed by potassium K+ ions, then calcium Ca2+ ions, then magnesium Mg2+ ions, and finally various positively charged proteins.

The majority of anions are chloride Cl− ions, followed by bicarbonate HCO3− ions, then phosphate PO43- ions, then sulfate SO42- ions, and finally some organic acids and negatively charged plasma proteins, like albumin.

So, to prove that there’s electroneutrality, let’s say we try to measure the concentration of the cations and anions in our plasma.

Unfortunately, not all of the ions are easy or convenient to measure. Specifically, among cations, usually just sodium Na+ is measured, which is typically around 137 mEq/L and among anions, chloride Cl− is measured, which is about 104 mEq/L, and bicarbonate HCO3− is measured, which is around 24 mEq/L.

So just counting up these three ions, there’s a difference, or “gap” between the sodium Na+ concentration and the sum of bicarbonate HCO3− and chloride Cl− concentrations in the plasma, which is 137 minus 128 (104 plus 24) or 9 mEq/L.

This is known as the anion gap, or in other words, how many more cations are there than anions.

Now just a few moments ago, we said that cations equal anions, so why does this gap even exist? Well, it’s because sodium Na+ accounts for the vast majority of cations in the plasma, but by measuring only chloride Cl− and bicarbonate HCO3−, we are ignoring a bunch of anions, including the anion component of several organic acids and negatively charged plasma proteins, like albumin.

In other words, this anion gap represents all these unmeasured, ignored negative charges out there, and normally, ranges between 3 and 11 mEq/L.

If the anion gap is high, it’s usually because there’s an unusually high amount of these unmeasured anions.

Calculating the anion gap is a useful diagnostic tool, because it can help identify potential causes of metabolic acidosis.

“Acidosis” refers to a process that lowers blood pH to less than 7.35 and “metabolic” refers to the fact that it’s caused by a decrease in the concentration of bicarbonate HCO3− ions.

One way that the bicarbonate HCO3− ion concentration decreases is by binding of bicarbonate HCO3− ions and protons H+, which results in the formation of H2CO3 carbonic acid, which subsequently breaks down into carbon dioxide CO2 and water H2O. These protons come off of various organic acids.

For example, in cases of heart failure, when not enough blood is pumped to the tissues, the cells won’t have much oxygen to break down glucose, so they will be forced to accumulate lactic acid molecules- each of which has a proton to donate. That’s known as lactic acidosis.

Another situation might be diabetic ketoacidosis which leads to the buildup of ketoacids, which are also molecules that carry along a proton.

Another situation might be after accidental ingestion of ethylene glycol, which is a common antifreeze. This can cause oxalic acid to build up.

A metabolite of methanol, a highly toxic alcohol, is formic acid.

Paint or glue has a molecule called toluene, which leads to a buildup of hippuric acid.

Organic acids, such as uric acid or sulfur- containing amino acids, might also build up in chronic renal failure, because the kidneys simply can’t get rid of them.

Alright, so say you have one of these organic acids, and then a sodium ion and a bicarbonate ion, so one positive and one negative ion, meaning we have electroneutrality. At a physiologic pH, these organic acids dissociate into protons H+ and corresponding organic acid anions. Protons H+ quickly grab bicarbonate HCO3− ions floating around.


The plasma anion gap is the difference between the plasma concentration of Na+ sodium and the sum of plasma concentrations of (Cl �� + HCO3 ��) and represents the unmeasured anions in the plasma. The normal range of plasma anion gap is between 3 �11 mEq/L. It is elevated in organic acid metabolic acidosis, such as lactic acidosis and diabetes ketoacidosis. Its decrease can be seen in cases of metabolic alkalosis, meaning that the body is producing too little acid or eliminating too much acid.